Heimler Syndrome 2

A number sign (#) is used with this entry because of evidence that Heimler syndrome-2 (HMLR2) is caused by compound heterozygous mutation in the PEX6 gene (601498) on chromosome 6p21.

Description

Heimler syndrome, which represents the mildest end of the peroxisomal biogenesis disorder spectrum (see PBD1A, 214100), is a rare autosomal recessive disorder characterized by sensorineural hearing loss, enamel hypoplasia of the secondary dentition, and nail abnormalities (Ratbi et al., 2015).

For a discussion of genetic heterogeneity of Heimler syndrome, see HMLR1 (234580).

Clinical Features

Ong et al. (2006) reported monozygotic twin girls who both had mild clubfeet at birth that responded to orthotics. At 3 years of age, the twins underwent audiography due to concerns about indistinct speech and poor vocabulary, which revealed moderate to severe bilateral sensorineural hearing loss. Primary teeth erupted normally; however, at age 10 years, abnormalities in their secondary dentition became evident, with the enamel on all 4 first permanent molars appearing pitted, grooved, and deficient in quantity. Dental radiography showed the presence of all permanent teeth, with hypoplasia or hypocalcification of the lower canines, premolars, and molars, as well as the unerupted upper second and third molars. Maxillary molars exhibited taurodontism (abnormally enlarged pulp chambers). In addition, there was marked dental overcrowding. Examination showed transverse ridges (Beau lines) on some of the toenails and leukonychia of the fingernails of both girls. Thumbs were slightly broad, and both girls exhibited pes planus. Intellectual development was normal.

Molecular Genetics

In 2 sisters from the UK with Heimler syndrome, Ratbi et al. (2015) performed whole-exome sequencing and identified compound heterozygosity for missense mutations in the PEX6 gene, P274L (601498.0010) and R644W (601498.0011). Sanger sequencing of the PEX1 (602136) and PEX6 genes in the monozygotic twin girls with Heimler syndrome who were originally reported by Ong et al. (2006) revealed compound heterozygosity for a frameshift (601498.0012) and a missense mutation (R601Q; 601498.0013) in the PEX6 gene. Ratbi et al. (2015) noted that, in contrast to patients with peroxisomal biogenesis disorders of the Zellweger type that are also caused by mutation PEX6 (see PBD4A, 614862), none of the patients with PEX6-associated Heimler syndrome exhibited dysmorphism or additional neurologic features.